Major Biosynthetic Pathways Cyclooxygenase COX

COX catalyzes two enzymatic activities; namely, the conversion of AA to the hydroperoxy endoperoxide PGG2, followed by its subsequent reduction to the labile product PGH2. PGH2 is the common substrate for a number of different cell-specific synthases, which convert PGH2 to the individual PGs or TX, including PGE2, PGI2 (prostacyclin), PGD2, PGF2a, and TXA2 (Figure 3). Two isoforms of COX named

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Membrane phospholipids

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Phospholipase A2

Arachidonic acid

Arachidonic acid

Figure 2 Metabolism of arachidonic acid to either the prostaglandins and thromboxane via the cyclooxygenase pathway or leukotrienes (and HETEs, lipoxins) via the lipoxygenase pathway. The isoprostanes and cyclopentaenone PGs are generated by nonenzymatic oxidation (dashed boxes). The epi-lipoxins are formed via interactions with cyclooxygenase and aspirin.

Figure 2 Metabolism of arachidonic acid to either the prostaglandins and thromboxane via the cyclooxygenase pathway or leukotrienes (and HETEs, lipoxins) via the lipoxygenase pathway. The isoprostanes and cyclopentaenone PGs are generated by nonenzymatic oxidation (dashed boxes). The epi-lipoxins are formed via interactions with cyclooxygenase and aspirin.

COX-1 and COX-2 were identified in the early 1990s and this led to renewed interest in the field of PG biology. Both isoforms catalyze the same reactions but are produced by different genes and although they share only about 61% sequence identity, the 3-dimensional crystal structures are virtually identical. After the discovery of the two isoforms, it quickly became apparent that their roles in many physiological processes were distinctive and that their expression and tissue profiles were differentially regulated. In general terms, COX-1 is constitutively expressed in most tissues and cell types and is responsible for the synthesis of the PGs required for the maintenance of normal physiology in the noninflamed state. Whereas COX-2 is generally undetectable in most tissues, its expression can be rapidly induced by a variety of inflammatory stimuli, such as bacterial LPS, cyto-kines, and growth factors. It is this isoform that synthesizes most PGs in inflammation and carcino-genesis. However, this division of the biological roles of COX-1 (physiological PGs) and COX-2 (inflammatory PGs) is an oversimplification of the biological reality. More recent studies have shown COX-1 can be induced or upregulated under certain conditions and that COX-2 is constitutively expressed in the brain and kidney. Thus, both COX-1 and COX-2 are involved in physiological as well as pathological responses.

The COX pathway is of major clinical importance because it is the major pharmacological target of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. Inhibition of PG synthesis is considered the primary mechanism responsible for both the therapeutic (anti-inflammatory, analgesic) and the toxic effects of NSAIDs. The clinically significant side effects of NSAIDs include renal impairment, dyspepsia, and upper gastrointestinal bleeding, the latter being particularly associated with inhibition of COX-1. By comparison, the anti-inflammatory and analgesic effects are associated with COX-2 inhibition. These observations provided the rationale for fast-track development of selective COX-2 inhibitors, which were promoted under the premise that they would have similar anti-inflammatory efficacy to conventional NSAIDs but would have significantly

Induces release of reactive oxygen species and hydrolytic enzymes by neutrophils

Potent bronchoconstrictor Promotes vasoconstriction fewer gastrointestinal (GI) side effects. Highly selective COX-2 inhibitors have been relatively successful with regard to their reduced GI toxicity. However, based on the role of COX-2 derived PGs in normal physiology, there exists the potential for other side effects such as increased cardiovascular events for at-risk patients and aggravated renal impairment in patients with reduced renal function.

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